Benzimidazole derivatives and pharmacologically acceptable salts thereof

ABSTRACT

This invention provides a compound having both IL-4 production inhibitory activity and PDE (IV) inhibitory activity, represented by formula (I):                    
     and a pharmaceutical composition or a therapeutic agent for acute and chronic inflammatory diseases and an anti-allergic or anti-inflammatory agent, each of which comprising an effective amount of the compound and a pharmacological carrier. It also provides use of the compound of formula (I) for the production of the aforementioned pharmaceutical composition or therapeutic agent for acute and chronic inflammatory diseases and anti-allergic or anti-inflammatory agent, and a method for treating acute and chronic inflammatory diseases.

This application is a 371 of PCT/JP98/05011 filed Nov. 6, 1998.

TECHNICAL FIELD

This invention relates to benzimidazole derivatives andpharmacologically acceptable salts thereof, which have both of aninterleukin (IL)-4 production inhibitory activity and aphosphodiesterase IV (PDE (IV)) inhibitory activity and are useful astherapeutic or preventive drugs for acute and chronic inflammatorydiseases such as atopic dermatitis, allergic rhinitis, bronchial asthmaand glomerulonephritis. It also relates to a pharmaceutical compositionin which the compound of this invention is used.

BACKGROUND ART

Regarding inflammatory diseases, various medicaments capable ofinhibiting acute stage inflammations have been developed in recentyears, but medicaments which can effectively inhibit chronic stageinflammations are still scarce so that their development is a pressingproblem. Also, an anti-inflammatory drug which can be used withoutdistinctions between acute stage and chronic stage is useful in theclinical field.

Under such circumstances, attempts are being made on the research anddevelopment of medicaments having phosphodiesterase IV (PDE (IV))inhibitory activity. This is based on the information that PDE (IV) isconcerned in acute and chronic inflammatory diseases (see for example,J. Pharmacol. Exp. Ther., 266(1), 306-313 (1993), Br. J. Pharmacol. ,120(2), 289-297 (1997) and Am. J. Respir. Crit. Care Med., 149(5),1153-1159 (1994)). In reality, however, drugs so far developed merelyhaving such an activity are effective for acute inflammatory diseasesbut cannot exert sufficient effects on chronic inflammatory diseases. Itis considered that certain members of cytokine produced by Th2 cells asone of the subgroups of CD4⁺ T cells are taking an important role in theonset of inflammatory diseases, and interleukin (IL)-4 among them isparticularly concerned in chronic stage inflammatory diseases (see forexample, Am. J. Physiol., 272 (2 Pt 1), L 253-261 (1997), Am. J. Respir.Cell Mol. Biol. , 10(5), 526-532 (1994) and ibid., 13(1), 54-59 (1995)).

In consequence, development of a drug having both PDE (IV) inhibitoryactivity and IL-4 production inhibitory activity will result in ananti-inflammatory drug which is effective on both acute and chronicinflammatory diseases. At present, PDA-641 has been reported as such acompound (cf. Allergy Clin. Immunol., 93, 286 (1994)), but this compoundis not satisfactory because of its weak IL-4 production inhibitoryactivity.

Benzimidazole derivatives have been broadly studies as medicaments.JP-A-3-14579 describes a benzimidazole derivative having an imidazolegroup and a triazole group, but the compound is disclosed only as atherapeutic agent for heart diseases and a therapeutic agent forduodenal ulcer, so that the compound has not been known as ananti-inflammatory agent (the term “JP-A” as used herein means an“unexamined published Japanese patent application”). InternationalPublication No. WO 94/12461 describes a benzimidazole derivative whichhas PDE (IV) inhibitory activity and is used in various inflammatorydiseases, but the benzimidazole derivative is different from thecompound of the present invention in terms of the presence or absence oftriazole ring on the condensed phenyl ring, and its effects on bothacute and chronic inflammatory diseases are not as expected.

The present invention contemplates providing a compound which has bothIL-4 production inhibitory activity and PDE (IV) inhibitory activity andis useful in treating or preventing acute and chronic inflammatorydiseases.

DISCLOSURE OF THE INVENTION

As a result of the extensive investigation, the inventors of the presentinvention have found that the aforementioned object can be achieved by anovel benzimidazole derivative in which a triazole group is introducedinto the 5-position of the benzinidazole nucleus, and substitutingpositions of two alkoxy groups to be substituted on the phenyl groupbonded to the 2-position are specified, thereby resulting in theaccomplishment of this invention.

Accordingly, the present invention relates to a benzimidazole derivativerepresented by formula (I):

[wherein A represents a triazole group; R₁ and R₂ may be the same ordifferent from each other and each represents an aliphatic hydrocarbonradical which may have an alicyclic or aromatic hydrocarbon radical oran alicyclic hydrocarbon radical; R₃ represents a hydrogen atom or asubstituent group; and R₄ represents a hydrogen atom or a protectivegroup of the nitrogen atom] or a pharmacologically acceptable saltthereof.

The benzimidazole derivative represented by the just described formula(I) or a pharmacologically acceptable salt thereof (hereinafter,referred to as “compound of the present invention”) has excellentactions of both IL-4 production inhibitory activity and PDE (IV)inhibitory activity and is useful for the treatment of various acute andchronic inflammatory diseases.

Thus, the present invention provides a pharmaceutical composition whichcomprises an effective amount of the compound of the present inventionand a pharmacological carrier.

It particularly provides an anti-allergic or anti-inflammatory agentwhich comprises an effective amount of the compound of the presentinvention and a pharmacological carrier.

The present invention also provides use of the compound of the presentinvention for the production of the aforementioned pharmaceuticalcomposition, therapeutic or preventive agent for acute and chronicinflammatory diseases and anti-allergic or anti-inflammatory agent.

The present invention further provides a method for treating and/orpreventing acute and chronic inflammatory diseases, which comprises thestep of administering an effective amount of the aforementioned compoundof the present invention to patients.

According to the present invention, examples of the triazole group of Ainclude 1,2,4-triazol-1-yl, 1,2,4-triazol-4-yl, 1,2,3-triazol-1-yl and1,2,3-triazol-2-yl, of which 1,2,4-triazol-1-yl and 1,2,4-triazol-4-ylare preferred and 1,2,4-triazol-1-yl is more preferred.

Examples of the aliphatic hydrocarbon radical in R₁ or R₂includestraight- or branched-chain lower alkyl groups having 1 to 6 carbonatoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl and n-hexyl; and straight- orbranched-chain lower alkenyl groups having 2 to 6 carbon atoms, such asvinyl, 1-propenyl, allyl, dimethylallyl, isopropenyl, 1-butenyl,2-butenyl, 1-methyl-2-butenyl, 1,3-butanedienyl, 1-pentenyl, 2-pentenyl,2-hexenyl and 1,4-hexanedienyl; of which straight- or branched-chainlower alkyl groups having 1 to 6 carbon atoms are preferred, and methyl,isopropyl and isopentyl are particularly preferred.

Examples of the aliphatic hydrocarbon radical having an alicyclichydrocarbon radical according to R₁ or R₂ include the aforementionedaliphatic hydrocarbon radicals further having monocyclic alicyclichydrocarbon radicals having 3 to 7 carbon atoms, which may have astraight- or branched-chain saturated lower alkyl group having 1 to 3carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, 3-isopropyl-cyclohexyl, cyclohexenyl,2-methyl-2-cyclohexenyl, 3-methyl-2-cyclohexenyl,4-ethyl-2-cyclohexenyl, cycloheptanyl and cycloheptenyl; or havingalicyclic hydrocarbon radicals of cross-linked ring or polycyclicsystem, such as bicyclobutanyl, bicyclooctanyl, norbornyl, norborenyland indanyl; and preferred are straight- or branched lower alkyl groupshaving 1 to 6 carbon atoms substituted with a monocyclic alicyclichydrocarbon radical having 3 to 7 carbon atoms, more preferablycyclopropylmethyl and cyclopentylmethyl.

Examples of the aliphatic hydrocarbon radical having an aromatichydrocarbon radical according to R₁ or R₂ include the aforementionedaliphatic hydrocarbon radicals further having an aromatic hydrocarbonradical such as phenyl or naphthyl, of which an aliphatic hydrocarbonradical having phenyl group is preferred, and benzyl, phenylethyl,phenylpropyl and cinnamyl are particularly preferred.

Examples of the alicyclic hydrocarbon radical according to R₁ or R₂include the aforementioned monocyclic alicyclic hydrocarbon radicalshaving 3 to 7 carbon atoms, which may have a straight- or branched-chainsaturated lower alkyl group having 1 to 3 carbon atoms, and theaforementioned alicyclic hydrocarbon radicals of cross-linked ring orpolycyclic system, of which monocyclic alicyclic hydrocarbon radicalshaving 3 to 7 carbon atoms are preferred, and cyclopentyl,cyclopentenyl, cyclohexenyl and cycloheptenyl are particularlypreferred.

Among compounds of the present invention, certain compounds havingasymmetric carbons exist in optical isomer forms and geometrical isomerforms depending on the number of asymmetric carbons, and all of theseisomers are included in the present invention.

Though conventionally used optical resolution methods can be used forthe isolation of optically active substances of the compound of thepresent invention, the optically active substances can also be obtainedby fractionating them by HPLC using an optically active column. Anexample of the optically active column is CHIRALPAK AD manufactured byDaicel Chemical Industries.

R₃ is a hydrogen atom or a substituent group, and examples of thesubstituent group include a lower alkoxy group, a lower alkyl group, ahydroxyl group, a nitro group, a cyano group, an amino group and ahalogen atom, but R₃ is preferably a hydrogen atom or a lower alkoxygroup. Examples of the lower alkoxy group include straight- orbranched-chain alkoxy groups having 1 to 6 carbon atoms, such asimethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,sec-butoxy, tert-butoxy, n-pentyloxy, cyclopentyloxy, isopentyloxy,n-hexyloxy and cyclohexyloxy, of which methoxy, ethoxy and pentyloxy arepreferred, and methoxy and n-pentyloxy are more preferred. Examples ofthe lower alkyl group include straight- or branched-chain alkyl groupshaving 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl and n-hexyl,of which methyl and ethyl are preferred. Examples of the halogen atominclude fluorine, chlorine, bromine and iodine.

The substituent group of R₃ can be substituted at least at one of the4-, 6- and 7-positions of the benzimidazole nucleus, but preferably atthe 6-position.

The nitrogen atom-protective group of P may be any group which can behydrolyzed easily in the living body, and its examples include acylgroups such as acetyl, benzoyl and pivaloyl; alkoxycarbonyl groups suchas methoxycarbonyl, ethoxycarbonyl and benzyloxycarbonyl;aryloxycarbonyl groups such as phenoxycarbonyl; straight- orbranched-chain lower alkyl groups having 1 to 6 carbon atoms, such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl and n-hexyl; hydroxy lower alkyl groupssuch as hydroxymethyl and hydroxyethyl; aralkyl groups such as benzyland trityl; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl,methoxyethyl and ethoxyethyl; alkoxyalkoxyalkyl groups such asmethoxymethoxymethyl, methoxyethoxymethyl, ethoxyethoxymethyl andethoxyethoxyethyl; and aralkyloxyalkyl groups such as benzyloxymethyl,trityloxymethyl, benzyloxyethyl and trityloxyethyl.

Examples of the pharmacologically acceptable salt of the benzimidazolederivative of the present invention represented by the formula (I)include mineral acid salts such as hydrochloride, sulfate and nitrate,and organic acid salts such as fumarate, maleate, tartarate,toluenesulfonate and methanesulfonate.

The compound of the present invention may exist in tautomer forms basedon the benzimidazole skeleton, and such isomers are also included in thepresent invention.

Also, the compound of the present invention may be in the form ofsolvates including hydrates, and amorphous or polymorphic forms.

Regarding the aforementioned formula (I), preferred is a benzimidazolederivative or a pharmacologically acceptable salt thereof, in which A is1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl, R₁ and R₂ may be the same ordifferent from each other and each is a straight- or branched loweralkyl group having 1 to 6 carbon atoms, which may have a monocyclicalicyclic hydrocarbon radical having 3 to 7 carbon atoms, or amonocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, R₃is a hydrogen atom or a lower alkoxy group and R₄ is a hydrogen atom,and more preferred is a benzimidazole derivative or a pharmacologicallyacceptable salt thereof, in which A is 1,2,4-triazol-1-yl, R₁ and R₂ maybe the same or different from each other and each is methyl, isopropyl,isopentyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentyl,cyclopentenyl, cyclohexenyl or cycloheptenyl, R₃ is a hydrogen atom andR₄ is a hydrogen atom.

The benzimidazole derivative of the present invention represented by theformula (I) can be produced using various compounds as the materials.For example, the benzimidazole derivative is produced by a method shownby the following reaction process A, in accordance with the methodsdescribed in “Heterocyclic Compounds Benzimidazoles and CongericTricyclic Compounds, Part 1,2” edited by P. N. Preston and“Comprehensive Heterocyclic Chemistry, Vol.5” edited by A. R. Katritzkyand C. W. Rees.

In the above formulae, A, R₁, R₂ and R₃ are as defined in the foregoing,and X is a halogen atom.

Illustratively, each step of the above reaction process A is carried outin the following manner.

(Step a)

The compound represented by the formula (3) can be produced by allowingthe known compound (1) as disclosed, for example, in Journal of ChemicalSociety, Perkin Trans I, 2751 (1994) to react with the known compound(2) in N,N-dimethylformamide in the present of a base, in accordancewith the methods as disclosed, for example, in Journal of MedicinalChemistry, Vol. 35, No. 23, 4455-4463 (1992) and JP-A-3-14579.

Examples of the base include potassium carbonate, sodium carbonate andsodium hydride. In carrying out the reaction, 1 to 2 moles of thecompound (2) and base are used based on 1 mole of the compound (1). Thereaction temperature is generally from about 50 to 150° C., preferablyfrom 100 to 120° C. The reaction time is generally from 0.5 to 24 hours,preferably from 3 to 6 hours.

(Step b)

The compound represented by the formula (4) is produced by reducing thecompound represented by the formula (3). The reduction method may beselected from the following methods 1) to 3).

1) The compound is reduced by hydrogenation in an inert solvent in thepresence of a catalyst. The inert solvent is not particularly limited,with the proviso that it does not take part in the reaction, and itsexamples include methanol, ethanol and ethyl acetate. Examples of thecatalyst include palladium-carbon, Raney nickel and platinum oxide. Thecatalyst is used in an amount of from 0.1 to 0.5 g, based on 1 g of thecompound of formula (3). The reaction is carried out under a hydrogenpressure of from 1 to 20 kg/cm² at a reaction temperature of from roamtemperature to 60° C. for a period of from 1 to 4 hours.

2) The compound is reduced in an acidic or alkaline solvent in thepresence of a metal or metal salt. Examples of the metal and metal saltinclude zinc, aluminum, tin, iron, stannous chloride, ferrous chlorideand ferrous sulfate. Examples of the acidic solvent include acetic acid,hydrochloric acid and sulfuric acid, each alone or as a combination withwater, methanol or ethanol. Examples of the alkaline solvent includeliquid ammonia, sodium hydroxide aqueous solution and potassiumhydroxide aqueous solution. The metal or metal salt is used in an amountof from 3 to 50 moles, preferably from 5 to 10 moles, based on thecompound (3). The temperature of this reaction is generally from 50 to150° C., preferably from 80 to 120° C. The reaction is carried out for aperiod of from 0.5 to 24 hours, preferably from 2 to 6 hours.

3) The compound is reduced by hydrazine in an appropriate solvent in thepresence of a metal salt or metal oxide and activated carbon. Examplesof the metal salt and metal oxide include ferric chloride and ferricoxide. The solvent is not particularly limited, with the proviso that itdoes not take part in the reaction, and its examples include methanol,ethanol and ethyl acetate. The metal salt or metal oxide is used in anamount of from 0.6 to 1.0 mole %, activated carbon is used in an amountof {fraction (1/10)} by weight and hydrazine is used in an amount offrom 1.5 to 2.0 moles, based on the compound (2). The temperature ofthis reaction is generally from 50 to 100° C., preferably refluxtemperature of the solvent used. The reaction is carried out for aperiod of from 0.5 to 24 hours, preferably from 2 to 6 hours.

(Step c)

The benzimidazole derivative of formula (Ia) is produced by allowing thecompound of formula (4) to react with the benzaldehyde derivative offormula (5) in an appropriate solvent in the presence of an oxidizingagent or sodium hydrogen sulfite.

The solvent is not particularly limited, with the proviso that it doesnot take part in the reaction, and its examples include methanol,ethanol, dimethylformamide, dimethylacetamide and nitrobenzene. Thebenzaldehyde derivative (5) is used in an amount of from 1.0 to 1.5moles, the oxidizing agent is used in an amount of from 1.0 to 2.0 molesand sodium hydrogen sulfite, if used, is used in the same amount, basedon the compound (4). The reaction temperature is from 70 to 150° C., andthe reaction time is from 1 to 18 hours.

The benzaldehyde derivative of formula (5) can be produced in accordancewith the method described in Journal of Medicinal Chemistry, Vol. 37,pp. 1696-1703 (1994), using vanillin or isovanillin as the material andcarrying out its alkylation with corresponding alkyl halide inN,N-dimethylformamide in the presence of a base. Examples of the baseinclude potassium carbonate, sodium carbonate, sodium hydroxide,potassium hydroxide and sodium hydride. In carrying out the reaction, 1to 2 moles of an alkyl halide and 1 to 2 moles of a base are used basedon 1 mole of the starting material. The temperature of this reaction isgenerally from 50 to 150° C., preferably from 60 to 90° C. The reactiontime is generally from 0.5 to 24 hours, preferably from 4 to 8 hours.

The derivative can also be produced by carrying out alkylation of acorresponding alcohol compound with triphenylphosphine and diethylazodicarboxylate in tetrahydrofuran under dehydration. In carrying outthe reaction, 1 to 2 moles of the alcohol compound, triphenylphosphineand diethyl azodicarboxylate are used based on 1 mole of the startingmaterial. The reaction temperature is from room temperature to refluxtemperature of the solvent, and the reaction time is from 1 to 24 hours.

The compound (Ia) of the present invention thus obtained by theaforementioned reaction process A may has a protective group introducedto the nitrogen atom on the benzimidazole skeleton in accordance withordinary methods as disclosed, for example, in International PublicationNo. WO93/14083.

The compound of the present invention thus obtained by theaforementioned reaction process A can be easily isolated and purifiedfrom the reaction mixture by usually used separation and purificationmeans such as column chromatography, recrystallization and evaporationunder reduced pressure.

The pharmaceutical composition, therapeutic or preventive agent foracute and chronic inflammatory diseases and anti-allergic oranti-inflammatory agent of the present invention can be made intopharmaceutical preparation compositions in the usual way usingappropriate pharmaceutical carriers. Examples of the carriers to be usedinclude those which are generally used in drugs, such as a filler, abinder, a disintegrating agent, a lubricant, a coloring agent, a flavorcorrective, an order corrective and a surface active agent.

Dosage form of the pharmaceutical composition of the present inventionwhen used as a therapeutic agent in mammals including human is notparticularly limited and can be selected optionally depending on eachtherapeutic purpose, and its illustrative examples include parenteralpreparations such as injections, suppositories, external preparations(e.g., ointments and adhesives) and aerosols, and oral preparations suchas tablets, coated tablets, powders, granules, capsules, solutions,pills, suspensions and emulsions.

The aforementioned various drugs are made into pharmaceuticalpreparations by ordinary preparation methods known in the field.

In forming oral solid dosage forms such as tablets, powders andgranules, examples of the carriers to be used include fillers such aslactose, sucrose, sodium chloride, glucose, urea, starch, calciumcarbonate, kaolin, crystalline cellulose, silicic acid, methylcellulose, glycerol, sodium alginate and acacia, binders such as simplesyrup, glucose solution, starch solution, gelatin solution, polyvinylalcohol, polyvinyl ether, polyvinyl pyrrolidone, carboxymethylcellulose, shellac, methyl cellulose, ethyl cellulose, hydroxypropylcellulose, water, ethanol and potassium phosphate, disintegrating agentssuch as dry starch, sodium alginate, agar powder, laminaran powder,sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fattyacid esters, sodium lauryl sulfate, stearic acid monoglyceride, starchand lactose, disintegration inhibitors such as sucrose, stearic acid,cacao butter and hydrogenated oil, absorption accelerating agents suchas quaternary ammonium base and sodium lauryl sulfate, moisture keepingagents such as glycerol and starch, adsorbents such as starch, lactose,kaolin, bentonite and colloidal silica and lubricants such as purifiedtalc, stearic acid salt, boric acid powder and polyethylene glycol. Asoccasion demands, tablets can be made into coated tablets using usualcoatings, such as sugar coated tablets, gelatin coated tablets, entericcoated tablets, film coated tablets, double-layer tablets andmulti-layer tablets. In forming the dosage form of pills, examples ofthe carriers to be used include fillers such as glucose, lactose,starch, cacao butter, hardened plant oil, kaolin and talc, binders suchas powdered acacia, powdered tragacanth, gelatin and ethanol, anddisintegrating agents such as laminaran and agar.

Capsules are prepared by mixing the active ingredient with theaforementioned various carriers and filling appropriate capsules such ashard gelatin capsules or soft capsules with the mixture.

The dosage form of suppositories can be formed by adding an appropriateabsorption accelerating agent to carriers such as polyethylene glycol,cacao butter, lanolin, higher alcohol, higher alcohol esters, gelatin,semi-synthetic glyceride and Witepsol (trade name, manufactured byDynamite Novel).

Examples of the carriers to be used in forming the dosage form ofinjections include diluents such as water, ethyl alcohol, macrogol,propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol and polyoxyethylene sorbitan fatty acid esters, pHadjusting agents and buffers such as sodium citrate, sodium acetate andsodium phosphate, and stabilizing agents such as sodium pyrosulfite,ethylenediaminetetraacetic acid, thioglycollic acid and thiolactic acid.In this case, the pharmaceutical preparation may contain sodiumchloride, glucose or glycerol in an amount sufficient enough forpreparing isotonic solution. It may also contain other additives such asa solubilization assisting agent, a soothing agent and a localanesthetic. By adding these carriers, subcutaneous, intramuscular andintravenous injections can be produced in the usual way.

The liquid preparations may be aqueous or oily suspensions, solutions,syrups or elixirs, and they are prepared using general additive agentsin the usual way.

When the dosage form of ointments such as pastes, creams and gels areprepared, generally used materials such as a base, a stabilizing agent,a moistening agent and a preservative are formulated and mixed inresponse to each purpose and made into respective preparations. Examplesof the base to be used include white petrolatum, paraffin, glycerol, acellulose derivative, polyethylene glycol, silicon and bentonite.Examples of the preservative to be used include methylparahydroxybenzoate, ethyl parahydroxybenzoate and propylparahydroxybenzoate.

Adhesive preparations can be produced in the usual way by coating theaforementioned ointments such as creams, gels or pastes on aconventional support. Examples of the suitable support include woven ornon-woven fabrics made of cotton, rayon or chemical fiber and films andfoam sheets of polymers such as soft vinyl chloride, polyethylene andpolyurethane.

Amount of the compound of the present invention to be contained in theaforementioned pharmaceutical preparations varies depending on variousconditions such as dosage form, route of administration and dosageregimen, so that the amount cannot be defined in a wholesale manner andshould be selected from a broad range for each case, but thepharmaceutical preparations may contain the compound generally in anamount of approximately from 1 to 70% by weight.

Administration methods of the aforementioned pharmaceuticalpreparations, such as intestinal application, oral administration,rectal administration, buccal application and percutaneous absorption,are not particularly limited but optionally decided depending, forexample, on the dosage form, the age, sex and other conditions of eachpatient and the degree of symptoms of each patient. For example, in thecase of tablets, pills, solutions, suspensions, emulsions, granules andcapsules, they are orally administered, and suppositories are used byrectal administration. In the case of injections, they are administeredby intravenous injection as such or after mixing with a usualreplacement solution such as of glucose or amino acids or, as occasiondemands, administered alone by intraarterial infusion, intramuscularinjection, intracutaneous injection, subcutaneous injection orintraperitoneal injection. Ointments are applied, for example, to theskin or oral mucous membrane.

Dose of the active ingredient of the pharmaceutical preparations of thepresent invention is optionally selected based on the applicationmethod, the age, sex and morbid state of each patient, kind of thecompound of the present invention to be administered and otherconditions, but it may be within the range of generally from 0.1 to1,000 mg/kg/day, preferably from 0.5 to 500 mg/kg/day. Thesepharmaceutical preparations of the present invention can be administeredby dividing the daily dose recited above into 1 to 4 doses per day.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing powder X-ray diffraction of the compound 1-bobtained in Inventive Example 1b.

BEST MODE OF CARRYING OUT INVENTION

The following illustratively describes the present invention on novelcompounds among the compounds represented by the formula (1), withreference to reference, inventive and test examples, though theinvention is not restricted thereby.

REFERENCE EXAMPLE 1

Synthesis of 5-(1,2,4-triazol-1-yl)-2-Nitroaniline

A 10.0 g portion of 5-chloro-2-nitroaniline, 8.0 g of 1,2,4-triazole and16.0 g of potassium carbonate were suspended in 50 ml of DMF and stirredfor 5hours while heating at 130° C. The reaction solution was pouredinto ice water, and the thus precipitated crystals were collected byfiltration and washed with purified water. By washing the crystals withmethanol, 10.0 g (84% in yield) of the title compound was obtained. Itsphysical property values are shown below.

m.p. 259-261° C.

¹H-NMR (DMSO-d₆): δ (ppm) 7.18 (1 H, dd, J=2.3, 9.4 Hz), 7.55 (1 H, d,J=2.3 Hz), 7.69 (2 H, br-s), 8.15 (1 H, d, J=9.2 Hz), 8.30 (1 H, s),9.37 (1 H, s)

REFERENCE EXAMPLE 2

Synthesis of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine

(1) A 20.0 g portion of 5-(1,2,4-triazol-1-yl)-2-nitroaniline obtainedby the method of Reference Example 1 was suspended in 400 ml ofmethanol, and the suspension was mixed with 5.0 g of 10%palladium-carbon catalyst and subjected to hydrogenation using a Parrtype reducing apparatus. When absorption of hydrogen was completed, thereaction solution was mixed with activated carbon and filtered throughCelite. The solvent was evaporated from the resulting filtrate, the thusobtained residue was mixed with ethyl acetate and then the thus formedcrystals were collected by filtration, thereby obtaining 14.0 g (82% inyield) of the title compound. Its physical property values are shownbelow.

m.p. 180-182° C.

¹H-NMR (DMSO-d₆): δ (ppn) 4.72 (2 H, br-s), 4.82 (2 H, br-s), 6.57 (1 H,d, J=8.3 Hz), 6.77 (1 H, dd, J=2.5, 8.3 Hz), 6.92 (1 H, d, J=2.5 Hz),8.07 (1 H, s), 8.89 (1 H, s)

(2) A 49.5 g portion of 5-(1,2,4-triazol-1-yl)-2-nitroaniline obtainedby the method of Reference Example 1 was suspended in 250 ml of 95%ethanol, and the suspension was mixed with 37.0 ml of 5 mol/l sodiumhydroxide aqueous solution and heated to 80° C. Next, a total it of 54.0g of zinc powder was added thereto in 5 g portions at intervals of 10minutes. After 1 hour of heating under reflux, the reaction mixture wasfiltered through Celite while it was hot, and then the resultingfiltrate was cooled.

Thereafter, the thus precipitated crystals were collected by filtrationand washed with cold ethanol to obtain 37.6 g (89% in yield) of thetitle compound. Its physical property values coincided with theaforementioned data.

(3) A 20.5 g portion of 5-(1,2,4-triazol-1-yl)-2-nitroaniline obtainedby the method of Reference Example 1 was suspended in 200 ml ofmethanol, and the suspension was mixed with 2.2 g of activated carbonand 160 mg of ferric chloride hexahydrate and refluxed for 15 minutes.Next, to this was added dropwise 15 g of 85% hydrazine monohydrate whilecontinuing the reflux. After 2 hours of reflux, insoluble matter wasremoved by Celite filtration, the solvent was evaporated from thefiltrate, ethyl acetate was added to the resulting residue and then thethus formed crystals were collected by filtration to obtain 16.4 g (94%in yield) of the title compound. Its physical property values coincidedwith the aforementioned data.

INVENTIVE EXAMPLE 1a

Synthesis of2-(3-isopropoxy-4-methoxyphenyl)-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 1-a]

(1) A 5.98 g portion of a known compound3-isopropoxy-4-methoxybenzaldehyde was added to 4.49 g of4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example2, and the mixture was stirred for 18 hours in 37 ml of nitrobenzenewhile heating at 150° C. After cooling, nitrobenzene was evaporatedunder a reduced pressure. By crystallizing the resulting residue withethyl acetate/hexane, 4.90 g (55%) of the title compound was obtained.Its physical property values are shown as the Compound No. 1 in Table 1.

(2) Under reflux, 20 ml of methanol solution containing 4.27 g of3-isopropoxy-4 -methoxybenzaldehyde and 10.81 g of ferric chloridehexahydrate was added dropwise to 35 ml of methanol solution containing3.50 g of 4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained inReference Example 2. The resulting mixture was refluxed for 1 hour andthen cooled, and the insoluble matter was collected by filtration. Thiswas suspended in ethyl acetate/water and alkalified with liquid ammonia,and then the insoluble matter was removed by Celite filtration. Theethyl acetate layer was collected and dried over magnesium sulfate, andthen the solvent was evaporated. By crystallizing the resulting residuewith ethyl acetate/hexane, 4.92 g (70%) of the title compound wasobtained. Its physical property values coincided with the data obtainedin the above step (1).

(3) A mixture consisting of 1.75 g of4-(1,2,4-triazol-1-yl)-o-phenylenediamine obtained in Reference Example2, 1.56 g of sodium hydrogen sulfite and 17 ml of dimethylacetamide washeated to 150° C., to which was subsequently added dropwise 17 ml ofdimethylacetamide solution containing 1.94 g of3-isopropoxy-4-methoxybenzaldehyde. After 2 hours of the reaction at thesame temperature, the solvent was evaporated under a reduced pressure.The resulting residue was shaken in ethyl acetate and 10% sodiumcarbonate aqueous solution to effect separation of layers, and theresulting ethyl acetate layer was collected. The ethyl acetate layer wasdried with magnesium sulfate, and then the solvent was evaporated. Bycrystallizing the resulting residue with ethyl acetate/hexane, 2.37 g(80%) of the title compound was obtained. Its physical property valuescoincided with the data obtained in the above step (1).

INVENTIVE EXAMPLE 1b

Synthesis of Amorphous2-(3-isopropoxy-4-methoxyphenyl)-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 1-b]

A 20 g portion of the title compound obtained by the just describedproduction method was suspended in 100 ml of water and heated to 80° C.Next, this was dissolved by adding 70 ml of methanol and cooled to roomtemperature, and then the resulting precipitate was collected byfiltration. This was air-dried and then heat-dried on phosphoruspentoxide under a reduced pressure to obtain 18.37 g (92%) of the titlecompound. Its physical property values are shown below. Also, its powderX-ray diffraction is shown in FIG. 1, which confirmed that the thusobtained compound is amorphous.

m.p. 118-126° C.

Elemental analysis data for C₁₉H₁₉N₅O₂·H₂O:

H C N Calcd. 5.54 64.54 19.84 Found 5.49 64.53 20.02

INVENTIVE EXAMPLE 2

Synthesis of2-(3-cyclopentyloxy-4-methoxyphenyl)-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 2]

The procedure of Inventive Example 1a-(1) was repeated, except that 1.00g of 3-cyclopentyloxy-4-methoxybenzaldehyde was used instead of3-isopropoxy-4-methoxybenzaldehyde, thereby obtaining 722 mg (34%) ofthe title compound. Its physical property values are shown in Table 1.

INVENTIVE EXAMPLE 3

Synthesis of2-(4-cyclopentyloxy-3-methoxyphenyl)-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 3]

The procedure of Inventive Example 1a- (1) was repeated, except that2.00 g of 4-cyclopentyloxy-3-methoxybenzaldehyde was used instead of3-isopropoxy-4-methoxybenzaldehyde, thereby obtaining 1.46 g (34%) ofthe title compound. Its physical property values are shown in Table 1.

INVENTIVE EXAMPLE 4

Synthesis of 2-(3,4-dimethoxyphenyl)-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 4]

The procedure of Inventive Example 1a-(1) was repeated, except that 949mg of veratraldehyde was used instead of3-isopropoxy-4-methoxybenzaldehyde, thereby obtaining 523 mg (28%) ofthe title compound. Its physical property values are shown in Table 1.

INVENTIVE EXAMPLE 5

Synthesis of2-(4-methoxy-3-n-pentyloxyphenyl)-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 5]

The procedure of Inventive Example 1a-(1) was repeated, except that 1.37g of 4-methoxy-3-n-pentyloxybenzaldehyde was used instead of3-isopropoxy-4-methoxybenzaldehyde, thereby obtaining 2.27 g (53%) ofthe title compound. Its physical property values are shown in Table 1.

INVENTIVE EXAMPLE 6

Synthesis of2-(3,4-dimethoxyphenyl)-6-methoxy-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 6]

A 1.06 g portion of 4-(1,2,4-triazol-1-yl)-5methoxy-o-phenylenediamineobtained in the same manner as described in Reference Examples 1 and 2was allowed to react with 949 mg of veratraldehyde by the method ofInventive Example 1a-(1), thereby obtaining 454 mg (25%) of the titlecompound. Its physical property values are shown in Table 1.

INVENTIVE EXAMPLES 7 TO 21

Each compound of the Compound Nos. 7 to 21 described in Table 1 wassynthesized by the same method of Inventive Example 1a-(3), with theirphysical property values also shown in Table 1.

INVENTIVE EXAMPLES 22 TO 26

Each compound of the Compound Nos. 23 to 27 described in Table 1 wassynthesized by the same method of Inventive Example 1a-(3), with theirphysical property values also shown in Table 1.

INVENTIVE EXAMPLE 27

2-{3-(2-Cyclohexenyloxy)-4-methoxyphenyl}-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 22]

The title compound having low melting point was obtained from the highmelting point compound obtained in Inventive Example 14, in accordancewith the method of Inventive Example 1b. Its physical property valuesare shown in Table 1.

INVENTIVE EXAMPLE 28

Resolution of Optically Active Substances of2-[3-(2-cyclohexenyloxy)-4-methoxyphenyl]-5-(1,2,4-triazol-1-yl)benzimidazole[Compound 14]

Using an optically active column, the compound 14 was fractionated byHPLC under the following conditions. As a result, (R)-isomer of thecompound 14 was obtained by collecting fractions at a retention time ofabout 35 minutes. Also, its (S)-isomer was obtained by collectingfractions at a retention time of about 40 minutes.

Column: CHIRALPAK AD (mfd. by Daicel Chemical Industries)

Developing solvent: n-hexane/denatured ethanol=90/10

Flow rate: 1.0 ml/min (L-6200 Intelligent Pump (mfd. by Hitachi Ltd.)was used)

Temperature: 40° C.

Detection: UV 254 nm (L-4000 UV Detector (mfd. by Hitachi Ltd.) wasused)

TABLE 1 Comp. Melting Point and No. Structure NMR Chemical Shift Value 1

m.p. 187-188° C. ¹H-NMR(DMSO-d₆):δ(ppm) 1.34(6H, d, J=6.1Hz), 3.85(3H,s), 4.68(1H, m), 7.16(1H, d, J=7.0Hz), 7.66-7.79(4H, m), 8.00(1H, br-s),8.23(1H, s), 9.28(1H, s), 13.00 (1H, br)  2

m.p. 122-127° C. ¹H-NMR(CDCl₃):δ(ppm) 1.55(2H, br-s), 1.79-1.86(6H, m),3.89(3H, s), 4.79(1H, br-s), 6.94(1H, d, J=8.3Hz), 7.52-7.86(5H, m),8.12(1H, s), 8.55(1H, s)  3

m.p. 194-196° C. ¹H-NMR(CDCl₃):δ(ppm) 1.60-1.98(8H, m), 3.86(3H, s),4.83(1H, m), 6.95(1H, d, J=8.3Hz), 7.52-8.00(5H, m), 8.13(1H, s),8.55(1H, s)  4

m.p. 213-215° C. ¹H-NMR(DMSO-d₆):δ(ppm) 3.86(3H, s), 3.90(3H, s),7.16(1H, d, J=8.3Hz), 7.64-7.80(4H, m), 7.90(0.5H, br-s), 8.10(0.5H,br-s), 9.28(1H, d, J=17Hz), 13.04(1H, br)  5

m.p. 185-187° C. ¹H-NMR(DMSO-d₆):δ(ppm) 0.92(3H, t, J=7.1Hz),1.35-1.50(4H, m), 1.76-1.87(2H, m), 3.86(3H, s), 4.05-4.10(2H, m),7.16(1H, d, J=8.9Hz) 7.67(1H, dd, J=1.7, 8.6Hz), 7.70(4H, d, J=8.7Hz),7.76-7.78(2H, m), 8.23(1H, s), 9.28(1H, s), 13.01.(1H, br)  6

m.p. 242-246° C. ¹H-NMR(DMSO-d₆):δ(ppm) 3.33(3H, s), 3.85(3H, s),3.89(3H, s), 7.14(1H, d, J=8.3Hz), 7.35(1H, br-s), 7.72-7.76(3H, m),8.19(1H, s), 8.87(1H, s), 12.89(1H, br)  7

m.p. 134-136° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.05(1H, br), 9.29(1H, s),8.24(1H, s), 8.00(1H, s), 7.85-7.69(4H, m), 7.32-7.28(2H, m),7.23-7.15(3H, m), 5.34(1H, m), 3.80(3H, s), 3.45(2H, dd, J=17.2, 5.9Hz),3.12(2H, dd, J=17.2, 2.3Hz)  8

m.p. 163-167° C. ¹H-NMR(DMSO-d₆)δ(ppm): 12.75(1H, br), 10.20(1H, s),8.92(1H, s), 8.18(1H, s), 7.71-7.68(3H, m), 7.19(1H, s), 7.13(1H, d,J=9.2Hz), 4.67(1H, m), 3.83(3H, s), 1.32(6H, d, J=5.9Hz)  9

m.p. 185-186° C. ¹H-NMR(DMSO-d₆)δ(ppm): 9.29(1H, s), 8.24(1H, s),8.01(1H, br-s), 7.80-7.65(4H, m), 7.16(1H, d, J=9.0Hz), 4.69(1H, m),3.89(3H, s), 1.31(6H, d, J=6.3Hz) 10

m.p. 118-120° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.04(1H, br), 9.29(1H,s),8.24(1H, s), 8.00(1H, br), 7.80-7.69(4H, m), 7.11(1H, d, J=8.6Hz),3.91(3H, s), 3.90(2H, d, J=6.9Hz), 1.27(1H, m), 0.64-0.57(2H, m),0.38-0.32(2H, m) 11

m.p. 193-194° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.01(1H, br), 9.28(1H, s),8.24(1H, s), 7.99(1H, br), 7.79-7.68(4H, m), 7.16(1H, d, J=8.4Hz),3.93(2H, d, J=6.9Hz), 3.87(3H, s), 1.30(1H, m), 0.66-0.59(2H, m),0.41-0.37(2H, m) 12

m.p. 161-164° C. ¹H-NMR(DMSO-d₆)δ(ppm): 12.85(1H, br), 8.84(1H, s),9.19(1H, s), 7.75(2H, s), 7.73(1H, s), 7.34(1H, br), 7.14(1H, d,J=8.9Hz). 4.67(1H, m), 4.09(2H, t, J=6.3Hz), 3.84(3H, s), 1.70(2H, m),1.33(6H, d, J=6.1Hz), 1.32(4H, m), 0.86(3H, t, d=6.7Hz) 13

m.p. 143-146° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.01(1H, br), 9.28(1H, s),8.24(1H, s), 8.00(1H, br), 7.79-7.67(4H, m), 7.16(1H, d, J=8.9Hz),4.32(1H, m), 3.86(3H, s), 1.99-1.63(4H, m), 0.98-0.92(6H, m) 14

m.p. 194-195° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.0(1H, br), 9.28(1H, s),8.23(1H, s), 7.99(1H, br), 7.81-7.65(4H, m), 7.17(1H, d, J=8.2Hz),6.00-5.86(2H, m), 4.93(1H, m), 3.85(3H, s), 2.06-1.65(6H, m) 15

m.p. 201° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.02(1H, br), 9.28(1H, s), 8.24(1H,s), 7.98(1H, br), 7.80-7.77(4H, m), 7.15(1H, m)3.86(3H, s), 3.86(2H, d,J=6.8Hz), 2.10(1H, m), 1.03(6H, d, J=6.6Hz) 16

m.p. 204-206° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.02(1H, br), 9.28(1H, s),8.23(1H, s), 7.99(1H, br), 7.79-7.66(4H, m), 7.15(1H, m), 3.86(3H, s),2.38(1H, m), 1.85-1.80(2H, m), 1.76-1.54(4H, m), 1.43-1.36(2H, m) 17

m.p.191-192° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.00(1H, br), 9.27(1H, s),8.23(1H, s), 8.00(1H, br), 7.81-7.68(4H, m), 7.43-7.22(4H, m), 7.45(1H,d, J=9.0Hz), 4.22(1H, m), 3.84(3H, s), 3.29(1H, m), 1.39(3H, d, J=7.1Hz)18

m.p. 214-216° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.04(1H, br), 9.29(1H, s),8.24(1H, s), 8.00(1H, br), 7.87-7.18(10H, m), 6.83(1H, d, J=16.0Hz),6.58(1H, td, J=16.0, 5.9Hz), 4.84(2H, d, J=5.4Hz), 3.88(3H, s) 19

m.p. 232-234° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.01(1H, br-s), 9.29(1H, s),8.24(1H, s), 8.01(1H, br-s), 7.78-7.66(4H, m), 7.15(1H, d, J=8.6Hz),4.36(1H, d, J=6.1Hz), 3.84(3H, s), 2.44(1H, br-s), 2.32(1H, s),1.90-1.87(2H, m), 1.66-1.44(4H, m), 1.27-1.15(3H, m) 20

m.p. 101-105° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.00(1H, br), 9.28(1H, s),8.23(1H, s), 8.00(1H, br), 7.80-7.68(4H, m), 7.36-7.15(6H, m), 4.77(1H,m), 3.85(3H, s), 3.09(1H, dd, J=13.7, 6.3Hz), 2.91(1H, dd, J=13.5,6.3Hz), 1.27(3H, d, J=5.9Hz) 21

m.p. 197-199° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.02(1H, br-s), 9.29(1H, s),8.25(1H, s), 8.01(1H, br), 7.82-7.67(4H, m), 7.15(1H, d, J=8.6Hz),5.52(1H, m), 4.63(1H, d, J=6.8Hz), 3.85(3H, s), 1.77(6H, d, J=5.1Hz) 22

m.p. 122-123° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.01(1H, d, J=8.2Hz), 9.28(1H,d, J=10.7Hz), 8.24(1H, d, J=4.9Hz), 8.10-7.63(4H, m), 7.17(1H, d,J=8.2Hz), 5.97(1H, dt, J=7.1, 3.2Hz), 5.88(1H, m), 4.93(1H, br-s),3.85(3H, s), 2.08-1.61(6H, m) 23

m.p. 197-198° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.01(1H, br), 9.28(1H, s),8.24(1H, s), 8.01(1H, br), 7.80-7.65(4H, m), 7.17(1H, d, J=9.1Hz),4.39(1H, m), 3.85(3H, s), 1.99(2H, m), 1.55(2H, m), 1.78-1.30(6H, m) 24

m.p. 135-140° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.01(1H, br), 9.28(1H, s),8.24(1H, s), 8.01(1H, br), 7.81-7.69(4H, m), 7.16(1H, d, J=8.4Hz),5.64(1H, br-s), 4.93(1H, br), 3.85(3H, s), 2.00-1.63(6H, m), 1.72(3H, m)25

m.p. 188-189° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.02(1H, br), 9.29(1H, s),8.24(1H, s), 8.00(1H, br), 7.80-7.67(4H, m), 7.18(1H, d, J=8.6Hz),5.95-5.78(2H, m), 5.08(1H, m), 3.86(3H, s), 2.27-2.19(2H, m),2.04-2.02(2H, m), 1.80-1.69(3H, m), 1.40-1.35(1H, m) 26

m.p. 140-144° C. ¹H-NMR(DMSO-d₆)δ(ppm): 13.03(1H, br), 9.29(1H, s),8.24(1H, s), 8.02(1, br), 7.82-7.68(4H, m), 7.16(1H, d, J=8.4Hz),6.20(1H, m), 6.04(1H, m), 5.49(1H, br-s), 3.99(3H, s), 2.54-2.37(3H, m),1.92-1.85(1H, m) 27

m.p. 132-134° C. ¹H-NMR(DMSO-d₆)δ(ppm): 12.98(1H, br), 9.28(1H, s),8.23(1H s), 8.00(1H, br), 7.81-7.67(4H, m), 7.15(1H, d, J=9.0Hz),5.80-5.57(2H, m), 4.97(1H, m), 3.85(3H, s), 1.64(3H, d, J=6.4Hz),1.40(3H, d, 6.1Hz)

In the above table, “Me” means a methyl group.

COMPARATIVE EXAMPLES

The following control compounds 1 to 5 were synthesized and used inpharmacological tests.

(1) Each of the control compounds 1 to 3 was synthesized in accordancewith the method described in JP-A-3-14579. Their physical propertyvalues are shown in the following.

(2) Each of the control compounds 4 and 5 was synthesized in accordancewith the method described in International Publication No. WO 94/12461.Their physical property values are shown below.

Control Compound 1

m.p. 264-266° C.

¹H-NMR (DMSO-d₆): δ (ppm) 7.77-7.86 (2 H, m), 8.12-8.14 (3 H, m), 8.26(1 H, s), 8.79-8.81 (2 H, m), 9.34 (1 H, s)

Control Compound 2

m.p. 230-232° C.

H-NMR (DMSO-d₆): δ (ppm) 3.88 (3 H, s), 4.05 (3 H, s), 6.73-6.79 (2 H,m), 7.64-7.72 (2 H, m), 8.04 (1 H, brs), 8.04-8.31 (2 H, m)r, 9.27 (1 H,s)

Control Compound 3

m.p. 189-190° C.

¹H-NMR (DMSO-d₆) δ (ppm) 3.87 (3 H, s), 4.04 (3 H, s), 6.72-6.79 (2 H,m), 7.11 (1 H, s), 7.39-7.42 (1 H, m), 7.71-7.84 (3 H, m), 8.20-8.29 (2H, m)

Control Compound 4

m.p. 244-246° C.

1H-NMR (DMSO-d₆): δ (ppm) 1.62-2.00 (8 H, m), 3.84 (3 H, s), 4.90-4.95(1 H, m), 7.14-7.17 (1 H, m), 7.62-8.19 (5 H, m)

Control Compound 5

m.p. 253-256° C.

¹H-NMR (DMSO-d₆): δ (ppm) 3.07-3.17 (2 H, m)r, 3.49-3.58 (2 H, m)), 3.84(3 H, s), 5.39-5.43 (1 H, m), 7.18-7.32 (5 H, m), 7.82-8.09 (4 H, m)),8.27 (1 H, s)

TEST EXAMPLE 1

Interleukin-4 (IL-4) Production Inhibitory Activity

This test was carried out in accordance with the method of Shelby et al.(J. Allergy Clin. Immunol., Vol. 100, No. 4, 511-519 (1997)). That is,CD4⁺T cells were purified from mouse spleen cells and suspended in 10%FCS-containing RPMI 1640 culture medium, and the cell suspension wasinoculated into wells of a 24 well culture plate, which had been coatedwith anti-rat IgG, at a density of 3×10⁶ cells per well. Anti-mouse CD3antibody and anti-mouse CD28 antibody were added thereto, and the cellswere cultured at 37° C. for 3 days in an atmosphere of 5% CO₂. The thusgrown cells were recovered, washed three times with HBSS (Hank'sbalanced salt solution) and then suspended in 10% FCS-containing RPMI1640 culture medium. The cell suspension was inoculated into wells of a24 well culture plate at a density of 1×10⁶ cells per well, mixed withIL-2 and cultured for additional 3 days. The resulting cells wererecovered, washed three times with HBSS and then suspended in 10%FCS-containing RPMI 1640 culture medium. The cell suspension wasinoculated into wells of a 24 well culture plate, which had been coatedwith anti-rat IgG, at a density of 2×10⁶ cells per well, anti-mouse CD3antibody and anti-mouse CD28 antibody were added thereto, and the cellswere again cultured for 1 day. The culture supernatant was recoveredfrom each well to measure the amount of produced IL-4 by ELISA. Eachdrug to be tested was treated at the time of the second addition ofanti-mouse CD3 antibody and anti-mouse CD28 antibody to calculate itsinhibition percentage based on the control IL-4 production by theaddition of the solvent alone, and IC₅₀ (50% inhibition concentration)of each drug to be tested was calculated based on the regression line.The results are shown in Table 2.

TEST EXAMPLE 21

Phosphodiesterase IV (PDE (IV)) Inhibitory Activity

Purification of PDE (IV) and measurement of its activity were carriedout by partially modifying the method of Saeki et al. (Biochem.Pharmacol., Vol. 46, 833-839, 1993). That is, PDE(IV) was purified bycentrifuging rat brain homogenate at 105,000×g, applying the resultingsupernatant to a Q-Sepharose column and then eluting the protein with adensity gradient of 0 to 0.5 M NaCl.

Activity of PDE(IV) was measured by the following two step procedure.Using 3H-cAMP (1 μM in final concentration) as the substrate, thereaction was carried out at 37° C. for 10 minutes in a reaction solutioncontaining tris(hydroxyl)aminomethane (50 mM, pH B8.0), EGTA (0.1 mM)and MgCl₂ (0.1 mM) and then the reaction was stopped by incubating thereaction solution at 95° C. for 5 minutes. The thus formed 5′-AMP washydrolyzed with 5′-nucleotidase, and AG1 X-8 resin was added thereto toeffect adsorption of unreacted CAMP. After centrifugation, 3H-adenosinewas counted using a scintillation counter. Each of the drugs to betested (compounds 1, 2 and 4) was added at the time of the commencementof reaction to calculate its inhibition percentage based on the controlin which the solvent alone was added, and IC₅₀ (50% inhibitionconcentration) of each drug to be tested was calculated based on theregression line. The results are shown in Table 2.

TABLE 2 IL-4 production inhibition PDE(IV) inhibition Compound No. IC₅₀(μM) IC₅₀ (μM) 1 4.3 0.02 11 5.5 1.6 14 6.1 0.54 18 5.1 0.051 25 2.80.73

TEST EXAMPLE 3

Ear Edema Reaction Inhibitory Activity in Mice [Test Inflammation]

This test was test was carried out in accordance with the method ofSawada et al. (Clin. Exp. Allergy, Vol. 27, pp. 225-231, 1996). Each ofBALB/c mice was immunized by the intraperitoneal injection of 1 μg ofegg albumin which had been adsorbed to 1 mg of ALUM. After 14 days ofthe immunization, ear edema reaction was induced by intracutaneousinjection of 1 μg of egg albumin into mouse earlobe. Ear edema (×10² mm)was calculated by measuring thickness of the ear before and 1 hour afterthe induction with a dial thickness gage (Peacok). Each of the drugs tobe tested (compounds 1 and 2) was suspended in 0.5%hydropropylmethylcellulose (HPMC) solution and orally administered 1hour before the reaction induction. Ear edema caused by the antigen wascalculated by subtracting ear edema after respective time of inductionin the case of the same treatment of normal mice, and the ear edemainhibition ratio (%) of the drugs to be tested was calculated based onthe solvent-administered (control) group. The results are shown in Table3.

The same test was carried out on the aforementioned control compounds 1to 5. The results are also shown in Table 3.

TEST EXAMPLE 4

Antigen-Induced Airway Reactivity Acceleration Inhibitory Activity inMice [Test on Chronic Inflammation]

The model for this test was prepared out in accordance with the methodof Nagai et al. (Life Sciences, Vol. 54, pp. 471-475, 1994). Each ofBALB/c mice was immunized by the intraperitoneal injection of 1 μg ofegg albumin which had been adsorbed to 1 mg of ALUM. After 14 days ofthe immunization, each animal was exposed to 1% egg albumin solutionusing an ultrasonic nebulizer, and this treatment was repeated threetimes at 3 day intervals. After 24 hours of the final exposure, theairway contraction reaction against intravenously injected acetylcholine(30 μg/animal) was measured as overflow volume (×0.01 ml) by themodified method of Konzett and Rossler under pentobarbital anesthesia.Each of the drugs to be tested (compounds 1 and 2) was suspended in 0.5%HPMC solution and orally administered once a day for a total of 10 daysstarting from the day before the antigen exposure until the day of finalexposure. Accelerated quantity of the airway contraction reaction causedby the antigen exposure was calculated by subtracting the contractionreaction against intravenously injected acetylcholine in the case of thesame treatment of normal mice, and the airway reactivity accelerationinhibition ratio (%) of the drugs to be tested was calculated based onthe solvent-administered (control) group. The results are shown in Table3.

The same test was carried out on the aforementioned control compounds 1to 5. The results are also shown in Table 3.

TABLE 3 Mouse ear edema Airway reactivity reaction inhibitionacceleration inhibition Compound No. (dose) (dose) Compound 1 60% (30mg/kg)  58% (10 mg/kg) Compound 2 78% (30 mg/kg)  47% (30 mg/kg) Controlcompound 1  2% (30 mg/kg)  26% (30 mg/kg) Control compound 2 17% (30mg/kg)  30% (30 mg/kg) Control compound 3 37% (30 mg/kg)   6% (30 mg/kg)Control compound 4  0% (100 mg/kg) −17% (30 mg/kg) Control compound 5 0% (100 mg/kg)  −3% (30 mg/kg)

Based on the results of the aforementioned Test Examples 1 and 2, it wasconfirmed that the benzimidazole compound of the present invention hasexcellent actions of both IL-4 production inhibitory activity and PDE(IV) inhibitory activity.

The compound of the present invention also showed excellent effects inthe acute and chronic inflammation tests of Test Examples 3 and 4.However, none of the control compounds 1 to 5 showed excellent effectsin these tests.

Next, formulation examples of the compound of the present invention areshown in the following.

[Formulation Example 1] Tablets Compound 1 200 mg Corn starch 50 mgMicrocrystalline cellulose 50 mg Hydroxypropylcellulose 15 mg Lactose 47mg Talc 2 mg Magnesium stearate 2 mg Ethyl cellulose 30 mg Unsaturatedglyceride 2 mg Titanium dioxide 2 mg

Tablets of 400 mg per one tablet having the above blending ratio wereprepared in the usual way.

[Formulation Example 2] Granules Compound 2 300 mg Lactose 540 mg Cornstarch 100 mg Hydroxypropylcellulose 50 mg Talc 10 mg

Granules of 1,000 mg per one package having the above blending ratiowere prepared in the usual way.

[Formulation Example 3] Capsules Compound 3 200 mg Lactose 30 mg Cornstarch 50 mg Microcrystalline cellulose 10 mg Magnesium stearate 3 mg

Capsules of 293 mg per one capsule having the above blending ratio wereprepared in the usual way.

[Formulation Example 4] Injections Compound 4 100 mg Sodium chloride 3.5mg Distilled water for injection use balance (2 ml per one ampoule)

Injections having the above blending ratio were prepared in the usualway.

[Formulation Example 5] Syrups Compound 5 200 mg Purified sucrose 60 mgEthyl parahydroxybenzoate 5 mg Butyl parahydroxybenzoate 5 mg Perfumeproper amount Coloring agent proper amount Purified water balance

Syrups having the above blending ratio were prepared in the usual way.

[Formulation Example 6] Suppositories Compound 6 300 mg Witepsol W-351,400 mg

(trade name, a mixture of mono-, di- and tri-glycerides of from lauricacid to stearic acid, manufactured by Dynamite Novel)

Suppositories having the above blending ratio were prepared in the usualway.

INDUSTRIAL APPLICABILITY

As described above, the benzimidazole derivatives of the presentinvention and a pharmacologically acceptable salt thereof have both ofIL-4 production inhibitory activity and PDE (IV) inhibitory activity andare useful as therapeutic and preventive drugs for acute and chronicinflammatory diseases such as atopic dermatitis, allergic rhinitis,bronchial asthma and glomerulonephritis. They are also useful astherapeutic and preventive drugs for autoimmune diseases such asrheumatism and multiple sclerosis, as well as insulin-resistant diabetesand AIDS.

What is claimed is:
 1. A benzimidazole derivative compound represented by formula (I):

wherein, A represents a triazole group; R₁ and R₂ may be the same or different from each other and each represents an aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical or an alicyclic hydrocarbon radical, wherein said aliphatic hydrocarbon radical may have a substituent group selected from a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain saturated lower alkyl group having 1 to 3 carbon atoms, an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system and a phenyl group, and said alicyclic hydrocarbon radical is a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain lower alkyl group having 1 to 3 carbon atoms or an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system; R₃ represents a hydrogen atom; and R₄ represents a hydrogen atom, or a pharmacologically acceptable salt thereof.
 2. The benzimidazole derivative compound or a pharmacologically acceptable salt thereof according to claim 1, wherein A is 1,2,4-triazol-1-yl.
 3. The benzimidazole derivative compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 2, wherein, the aliphatic hydrocarbon radical moiety of said aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical in R₁ or R₂ is a straight- or branched-chain lower alkyl group having 1 to 6 carbon atoms or a straight- or branched-chain lower alkenyl group having 2 to 6 carbon atoms.
 4. The benzimidazole derivative compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 2, wherein R₁ and R₂ may be the same or different from each other and each is a methyl, isopropyl, isopentyl, cyclopropylmethyl, cyclopentylmethyl, benzyl, phenylethyl, phenylpropyl, cinnamyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or cycloheptenyl group.
 5. The benzimidazole derivative compound or a pharmacologically acceptable salt thereof according to claim 1, wherein A is 1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl; R₁ and R₂ may be the same or different from each other and each is a straight- or branched lower alkyl group having 1 to 6 carbon atoms, which may have a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, or a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms; R³ is a hydrogen atom or a lower alkoxy group; and R⁴ is a hydrogen atom.
 6. The benzimidazole derivative compound or a pharmacologically acceptable salt thereof according to claim 5, wherein A is 1,2,4-triazol-1-yl; R₁ and R₂ may be the same or different from each other and each is a methyl, isopropyl, isopentyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentyl, cyclopentenyl, cyclohexenyl or cycloheptenyl group; R₃ is a hydrogen atom; and R₄ is a hydrogen atom.
 7. A pharmaceutical composition, comprising an effective amount of the compound of formula (I):

wherein, A represents a triazole group; R₁ and R₂ may be the same or different from each other and each represents an aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical or an alicyclic hydrocarbon radical, wherein said aliphatic hydrocarbon radical may have a substituent group selected from a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain saturated lower alkyl group having 1 to 3 carbon atoms, an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system and a phenyl group, and said alicyclic hydrocarbon radical is a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain lower alkyl group having 1 to 3 carbon atoms or an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system; R₃ represents a hydrogen atom; and R₄ represents a hydrogen atom, or a pharmacologically acceptable salt thereof; and a pharmacological carrier.
 8. A therapeutic agent for acute and chronic inflammatory diseases, comprising an effective amount of the compound of formula (I):

wherein, A represents a triazole group; R₁ and R₂ may be the same or different from each other and each represents an aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical or an alicyclic hydrocarbon radical, wherein said aliphatic hydrocarbon radical may have a substituent group selected from a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain saturated lower alkyl group having 1 to 3 carbon atoms, an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system and a phenyl group, and said alicyclic hydrocarbon radical is a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain lower alkyl group having 1 to 3 carbon atoms or an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system; R₃ represents a hydrogen atom; and R₄ represents a hydrogen atom, or a pharmacologically acceptable salt thereof; and a pharmacological carrier.
 9. An anti-allergic or anti-inflammatory agent, comprising an effective amount of the compound of formula (I):

wherein, A represents a triazole group: R₁ and R₂ may be the same or different from each other and each represents an aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical or an alicyclic hydrocarbon radical, wherein said aliphatic hydrocarbon radical may have a substituent group selected from a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain saturated lower alkyl group having 1 to 3 carbon atoms, an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system and a phenyl group, and said alicyclic hydrocarbon radical is a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain lower alkyl group having 1 to 3 carbon atoms or an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system; R₃ represents a hydrogen atom; and R₄ represents a hydrogen atom, or a pharmacologically acceptable salt thereof; and a pharmacological carrier.
 10. A method for treating acute and chronic inflammatory diseases, comprising the step of administering to patients an effective amount of the benzimidazole derivative compound represented by formula (I):

wherein, A represents a triazole group; R₁ and R₂ may be the same or different from each other and each represents and aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical or an alicyclic hydrocarbon radical, wherein said aliphatic hydrocarbon radical may have a substituent group selected from a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain saturated lower alkyl group having 1 to 3 carbon atoms, an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system and a phenyl group, and said alicyclic hydrocarbon radical is a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, which may have a straight- or branched-chain lower alkyl group having 1 to 3 carbon atoms or an alicyclic hydrocarbon radical of cross-linked ring or polycyclic system; R₃ represents a hydrogen atom; and R₄ represents a hydrogen atom, or a pharmacologically acceptable salt thereof.
 11. The benzimidazole derivative compound according to claim 1, wherein said derivative is


12. The benzimidazole derivative compound according to claim 1, wherein said derivative is


13. The pharmaceutical composition according to claim 7, wherein said compound is


14. The pharmaceutical composition according to claim 7, wherein said compound is


15. The therapeutic agent according to claim 8, wherein said compound is


16. The therapeutic agent according to claim 8, wherein said compound is


17. The anti-allergic or anti-inflammatory agent according to claim 9, wherein said compound is


18. The anti-allergic or anti-inflammatory agent according to claim 9, wherein said compound is


19. The method according to claim 10, wherein A is 1,2,4-triazol-1-yl.
 20. The method according to claim 10 or 19, wherein the aliphatic hydrocarbon radical moiety of said aliphatic hydrocarbon radical which may have an alicyclic or aromatic hydrocarbon radical in R₁ or R₂ is a straight- or branched-chain lower alkyl group having 1 to 6 carbon atoms or a straight- or branched-chain lower alkenyl group having 2 to 6 carbon atoms.
 21. The method according to claim 10 or 19, wherein R₁ and R₂ may be the same or different from each other and each is a methyl, isopropyl, isopentyl, cyclopropylmethyl, cyclopentylmethyl, benzyl, phenylethyl, phenylpropyl, cinnamyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or cycloheptenyl group.
 22. The method according to claim 10 or 19, wherein A is 1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl; R₁ and R₂ may be the same or different from each other and each is a straight- or branched-chain lower alkyl group having 1 to 6 carbon atoms, which may have a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms, or a monocyclic alicyclic hydrocarbon radical having 3 to 7 carbon atoms; R₃ is a hydrogen atom or a lower alkyl group; and R₄ is a hydrogen atom.
 23. The method according to claim 22, wherein A is 1,2,4-triazol-1-yl; R₁ and R₂ may be the same or different from each other and each is a methyl, isopropyl, isopentyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl or cycloheptenyl group; R₃ is a hydrogen atom; and R₄ is a hydrogen atom.
 24. The method according to claim 10 wherein the benzimidazole derivative compound is


25. The method according to claim 10 wherein the benzimidazole derivative compound is 